“There is mounting evidence that natural progesterone improves cardiovascular function in contrast to the synthetic progestin medroxyprogesterone acetate (MPA) used in the large scaled US investigations.”
“Progesterone is rapidly cleared from the blood, which can present challenges regarding serum progesterone testing.”
“Orally administered progesterone, even in micronized form, shows a wide variation of absorption and bioavailability in tti individual person.”

“HRT improved glycemic control in postmenopausal women with type 2 diabetes and accordingly may improve some aspects of the menopausal metabolic syndrome.”

“The combination of non-oral administration of estradiol and local delivery of a progestin such as levonogestrel by means of gels, sprays, vaginal rings or intrauterine systems represent new methods of replacement therapy for the menopausal woman, improving compliance and minimizing the risks”

“Greater than 90% of oral progesterone was found to be inactivated by enzymatic degradation in the gut and liver, resulting in low serum concentrations of the active steroid”

“The chemical structure of progesterone makes it rather hydrophobic, and the carrying capacity of plasma would, therefore, become low when it is not bound to the circulating proteins.”

“It is hypothesized that transdermally delivered progesterone is a substrate for peripheral 5 alpha-reductase, and conversion to 5 alpha-reduced progestin may be a significant factor accounting to low systemic progesterone levels and pregnanedio1-3- glucuronide excretion.”

“Progesterone cream has a similar effect on the endometrium as the standard oral progestogen”

This was a blinded study were participants were given daily 0.625mg of CEE and twice daily transdermal progesterone cream either 0%, 1.5 % or 4.0% for 28 days. An endometrial biopsy was performed after treatment. No increased risk of hyperplasia was found, and it was concluded that progesterone cream has an antiproliferative effect on the endometrium.

Vashisht, Arvind et al. “A study to look at hormonal absorption of progesterone cream used in conjunction with transdermal estrogen” in

“A key metabolic alteration that increases BC risk is the resistance to insulin action on carbohydrates (insulin resistance: reduced insulin sensitivity), due to genetic and nutritional factors, with consequent hyperinsulinemia.”

“High levels of free testosterone have been identified as a risk factor for BC both before and after menopause.”

“Estrogens, particularly orally administered estrogens, are able to counteract metabolic factors that increase the risk of BC.

“When combined with an estrogen, progesterone may have a safer risk profile in the breast compared with some other progestagens.”

“Our finding of a 1/3 fold increased breast cancer risk associated with the use of estrogen alone (almost exclusively estradiol compounds, and mostly administered through the skin) differs with that of the WHI estrogen-alone trial which found a decreased risk when oral conjugated equine estrogens were used in a population of older and often overweight women.

“After adjustment for confounding factors, ETS (transdermal) was associated with a statistically significant risk reduction for VTE and hospitalization-related VTE by 33% and 62%, respectively, compared with the oral estrogen-only HT cohort. Of note, the risk reduction associated with ETS was more pronounced for PE events.”

Maki, Pauline et al. “Summary of the National Institute on Aging-sponsored conference on depressive symptoms and cognitive complaints in the menopausal transition.” In Menopause. Vol.17. No. 4.2010. 815-822.

This was a meta-analysis looking at eight observational studies and nine randomized controlled trials.

“Meta-analysis of observational studies showed that oral estrogen but not transdermal estrogen increased the risk of venous thromboembolism. Compared with non-users of estrogen, the odds ration of first time venous thromboembolism in current users of oral estrogen was 2.5 and in current users of transdermal estrogen was 1.2.”

“No noticeable difference in the risk of venous thromboembolism was observed between unopposed oral estrogen and opposed oral estrogen.”

“This meta-analysis of observational studies and randomized controlled trials showed that current use of oral estrogen increases the risks of venous thromboembolism by twofold to threefold. This increased risk was higher within the first year of treatment and more pronounced for women at higher risk of venous thromboembolism.”

“Combined analysis of observational studies showed no significant increase in the risk of venous thromboembolism among women using transdermal estrogen.”

“Oral but not transdermal estrogen increases plasma concentrations of prothrombin fragment 1+2, which is a marker for in vivo thrombin generation and increases the fibrinolytic potential in postmenopausal women.”

“Early treatment of euthyroid Hashimoto’s thyroiditis patients with L-thyroxine may slow down not only the disease process itself but through its immune modulating events it may also affect the course of other auto-immune diseases which accompany.”

“Symptoms of androgen insufficiency most often reported in the literature include (1) a diminished sense of well-being or dysphoric mood; (2) persistent, unexplained fatigue; and (3) sexual function changes, including decreased libido, sexual receptivity, and pleasure.”

“A diagnosis of androgen insufficiency should only be made in women who are adequately estrogenized.”

“Free T values should be at or below the lowest quartile of the normal range for the reproductive age (20-40 years), in conjunction with the presence of clinical symptoms and adequate estrogen status.”

“The 5 alpha reductase and aromatase activities present in the epidermal layer of nongenital skin (such as the abdomen) are relatively small, the degree of first-pass dermal metabolism of testosterone to dihydrotestosterone (DHT) and estradiol (E2) is likewise expected to be small when using a non-genital transdermal patch”

Giving testosterone orally can cause “marked reductions in the concentrations of SHBG and thyroxine-binding globulin, which may impact hormone bioavailability, and HDL cholesterol, which may adversely affect cardiovascular risk.

“The individual patient who requires both testosterone and ET, the use of transdermal E2 would result in a substantially greater increase in free testosterone levels than if oral estrogen therapy were given concomitantly with a testosterone matrix patch”

“A major androgenic effect demonstrated in this in vivo study is the down-regulation of ER alpha and up-regulation of ER Beta expression, resulting in reversal of the ER alpha-dominant receptor ratio found in E2 treated mammary epithelium.”

“Interestingly, a reciprocal or inverse relationship between expressions of these two ERs is also reported I breast cancer tissues, where ER B expression is also inversely correlated with proliferation”

“With regard to the testosterone gel, maximum testosterone levels on day 1 of treatment … occurred at 4-18 hours after administration.”

“These data suggest that testosterone gel is the preferable route of administration of testosterone because the gel provides prolonged levels of total testosterone. The commonly prescribed doses of 1 mg of micronized testosterone gel. . appear(s) to be excessive.”

“The addition of androgens to HRT has been shown not only to improve sexual health but also to prevent bone loss. In fact, androgen receptors have been found in bone cells of both men and women. Whereas estrogen decreases bone resorption, androgens may promote bone deposition by increasing osteoblastic activity.”

“The addition of methyl-testosterone to HRT in postmenopausal women has been reported to adversely affect lipid profiles, and may have hepatotoxic effects.”

“The sublingual administration of micronized testosterone also avoids first passage through the liver, which may preclude the unfavorable lipoprotein effects.’

The study used either micronized estradiol 0.5mg or micronized estradiol 0.5mg plus micronized testosterone 1.25mg, and micronized progesterone 100mg if they had a uterus. This regimen was given BID.

“It has been suggested that progestogens may stimulate bone formation independent of estrogen. Although the synthetic nortestosterone-derived C19 progestins (i.e., noresthisterone) have been reported to have beneficial effects on bone density possibly because of their androgenic properties, the C21 progestins, MPA or P4 itself, have not consistently been shown to enhance bone metabolism.”

“A number of other small cohort and case-control studies have used HRT in women previously treated for breast cancer without adverse effect. None of these studies has shown an increased risk of recurrence.”

“There was no evidence from this study to indicate any difference in the risk of recurrence of breast cancer for women using topical vaginal estrogen therapy compared with those who use no hormonal therapy.”

“Limited systemic absorption has been reported with the use of vaginal estriol cream or suppositories, while marked systemic absorption can occur with Premarin cream. Endometrial proliferation has not been reported with vaginal estriol preparations.”

“Women with advanced breast cancer and acquired resistance to aromatase inhibitors were given either 6mg or 30mg daily of Estradiol. Patients showed an improvement in their disease when given Estradiol, but the 6 mg dose was better tolerated and had less side effects. “In conclusion, 6 mg of estradiol daily, which produces estradiol levels similar to those in ovulating premenopausal women, is an active low-cost treatment for postmenopausal women with advanced breast cancer and acquired resistance to aromatase inhibitor treatment and should be further investigated.”

“Adding progesterone to E2 significantly reduced the proliferative effect of E2 alone, The present data shows that in vivo, 10 to 13 days of P exposure decreases the growth fraction of normal epithelial cells in the breast of premenopausal women.”

“It also suggests that P or related drugs may have a therapeutic value to prevent breast epithelial hyperplasia when used > 10 days per month at approximate substitutive doses.”

“The association between HRT use and breast cancer risk most likely varies according to the type of progestogen used. There was no or little increase in risk with estrogens used alone or combined with micronized progesterone.”

“Women with elevated androgen levels, whether endogenous or exogenous, experience breast atrophy consistent with the notion that androgens, per se, are antiproliferative for the breast.”

“Androgens and DHEA, acting through the androgen receptor, have been shown in the vast majority of studies to inhibit estrogen-stimulated proliferation of human breast cancer cell lines.”

“DHEA stimulates bone formation through its androgenic or anabolic component (an effect not achieved with SERMs, bisphosphonates, estrogens or calcitonin, which only decrease the rate of bone resorption).”

“Vagifem, an estradiol tablet, when administered at the 25-mcg dose, led to serum E2 levels of 80pmol/ L with values still elevated but less than 50 pmol/L at 14 hours and later.”

“It does not appear reasonable or acceptable to increase serum E2 levels during breast cancer therapy when the objective of treatment with aromatase inhibitors is precisely to achieve maximal inhibition of E2 biosynthesis.”

Tamimi, Rulla M. et at “Combined Estrogen and Testosterone Use and Risk of Breast Cancer in Postmenopausal Women” in Archives of Internal Medicine. Vol.166. July 24, 2006. 1483-1489.

This was a prospective cohort study in the Nurses’ Health Study from 1978 to 2002 to assess the risk of breast cancer associated with different types of postmenopausal hormone formulations containing testosterone. The data was for estrogen only, testosterone only, and estrogen and testosterone therapies only.”

“This study … specifically addressed the effect of oral E&T therapy as currently used in US postmenopausal women on the risk of breast cancer.”

“Epidemiologic studies demonstrate that circulating levels of testosterone are associated with an increased risk of breast cancer among postmenopausal women, independent of circulating estrogen levels.”

“The majority of in vitro studies using breast cancer cell lines report that androgens have inhibitory effects on the proliferative effects of estrogen”

“These results are also consistent with studies showing that E&P therapies with synthetic testosterone-derived progestogens are associated with a greater risk of breast cancer compared with those with micronized progesterone.

“Four studies of patients using HRT, including either progesterone or MPA, compared efficacy, patient satisfaction, and quality of life. Women in all 4 studies reported greater satisfaction, fewer side effects, and improved quality of life when they were switched from synthetic progestins to progesterone replacement.”

“Synthetic progestins may also increase the conversion of weaker endogenous estrogens into more potent estrogens, potentially contributing to their carcinogenic effects, which are not apparent with progesterone.”

“Use of unopposed postmenopausal estrogen from ages 50-60 years increased the risk for breast cancer to age 70 by 23 %.”

“In contrast to the demonstrated increased risk for breast cancer with synthetic progestins, studies have consistently shown a decreased risk for breast cancer with progesterone.”

“Melamend et al demonstrated that, when administered with estradiol, estriol may have a unique ability to protect breast tissue from excessive estrogen-mediated stimulation. Acting alone, estriol is a weak estrogen, but when given with estradiol, it functions as an antiestrogen.”

“Postmenopausal women suffering from vaginal atrophy received daily DHEA or placebo intravaginally for 3 months. A rapid and very marked improvement of all the symptoms and signs of vaginal atrophy was observed, with no change in circulating estradiol or testosterone.”

“This marked reduction in the secretion of DHEA by the adrenals during aging results in a parallel fall in the formation of androgens and estrogens in peripheral target tissues, a situation believed to be associated with a series of medical problems of menopause: insulin resistance, fat accumulation, bone loss, muscle loss, type 2 diabetes, vaginal atrophy and skin atrophy, memory and cognition loss, and possibly Alzheimer’s disease.”

“These actions also indicate a unique activity of DHEA on bone (namely, a stimulation of bone formation) while ET, HT, bisphosphonates, selective estrogen-receptor modulators and calcitonin only reduce the rate of bone loss.”

“Compared to placebo, DHEA produced a 68% improvement in the ASF arousal/sensation domain, a 39% improvement in the arousal/ lubrication domain, a 75% improvement in orgasm, and a 57% improvement in dryness during intercourse.”

“There is no reason to believe that the metabolism, action and safety of exogenous DHEA given at physiologic doses to symptomatic women would be different from the metabolism and action of endogenous DHEA in women who have sufficient levels of DHEA to remain free from the symptoms of menopause.”

“This is well supported by the absence of DHEA-related safety issues in the medical literature, in which high doses of DHEA have been used orally or percutaneously in a large series of women for up to 2 years.”

“Following cessation of estrogen secretion by the ovaries in postmenopausal women, all estrogens and almost all androgens are made locally from DHEA in the peripheral target tissues with minimal diffusion of the active steroids outside these tissues.”

Subjects were given 3m1 twice daily of one of the 5 concentrations: Placebo, 0.1% DHEA, 0.3% DHEA, 1% DHEA, and 2% DHEA for 13 weeks.

“It is quite clear from the present data that DHEA is preferentially transformed into androgens rather than into estrogens in postmenopausal women.”

“The present data show for the first time that the intra-vaginal administration of DHEA can rapidly increase the maturation index and decrease the pH in vaginal atrophy. Most importantly, this effect is achieved while maintaining serum estrogen levels within the values found in normal postmenopausal women, this avoiding the risk of breast or uterine cancer.”

“It is of major interest that endometrial biopsies performed at the end of the 12-month therapy with a high daily DHEA dose (4g of a 10% DHEA cream applied on the skin) showed atrophy in all women, thus indicating that the human endometrium does not possess the enzymes required to transform DHEA into estrogens and eliminates the need for the addition of a progestin to avoid the risk of uterine cancer.”

“Our recent preclinical data have shown an important effect of DHEA on all three layers of the vaginal wall, including the collagen fibers of the lamina propria and the muscularis.”

“Although DHEA can be transformed into both androgens and estrogens in the mammary gland, the global effect of DHEA on the human mammary gland is inhibitory.”

“Because the only variable source of sex steroids available in postmenopausal women in DHEA secreted by the adrenals and locally transformed in specific cells and tissues into estrogens and/ or androgens by the mechanisms of intracrinology, replacement with DHEA seems to be the only physiological replacement therapy for postmenopausal women experiencing menopausal symptoms.”

“Salivary cortisol is a validated marker of free cortisol, although it is not commonly used in clinical practice”

“Oral oestrogen preparations as routinely used in the clinical setting result in marked increases in total cortisol concentrations due to increased CBG levels. Transdermal oestrogen preparations do not appear to alter CBG or cortisol concentrations.

“In a previous study, we had shown that in PMW the administration of a huge dose of melatonin (100mg) is capable of unmasking the critical regulation of HPA axis and markedly enhancing cortisol levels. The present study shows that this stimulatory effect of melatonin on cortisol is nullified by estrogen supplementation.”

“The possibility that estrogens improve the control of the HPA axis and reduce the increase of cortisol after stimulation and/or at selected circadian times, may prove important for the prevention of metabolic and cardiovascular alterations of postmenopausal women.”

“Several pieces of evidence indicate that depression and anxiety, whose scores increase in the perimenopause and early postmenopause, can be associated with elevated adrenocortical activity.” Head, Kathleen A. “Estriol: Safety and Efficacy” in Alternative Medicine Review. Volume 3, Number 2, 1998. “Estriol has a much lower affinity for binding to SHBG; therefore, a greater percent is available for biological activity.” “One mg intravaginal estriol resulted in serum levels equivalent to 10mg of the orally administered hormone.”

“When given alone, it generally exerts an estrogenic effect, the strength of which depends on the dosage. When given in conjunction with estradiol, it appears to exert antagonistic effects”

“Estriol succinate may have less thrombotic potential than synthetic estrogens” “Estriol appears very effective for the treatment of menopausally- related urinary incontinence, urgency, and persistent UTIs.” “Daily use of intravaginal estriol is safe and without risk of endometrial proliferation or hyperplasia.”

“Due to conflicting reports on the effect of estriol on the endometrium, it is probably wise to prescribe a natural progesterone in conjunction with the estriol for a period of at least 10-14 days per month in order to shed any uterine tissue which may have built up as a result of the estriol administration.”

“Estriol is probably a safer form of estrogen replacement in regard to breast cancer for the following reasons: 1) In vitro, when given in conjunction with estradiol, it accelerates the removal of estradiol bound to protein receptors; 2) investigators have been able to initiate very little carcinogenesis in animal studies unless large doses (200-500mcg/kg/day) were used on a continuous basis; 3) in animal studies it has been found to prevent carcinogen-induced mammary tumors; and 4) unlike estrone and estradiol, estriol metabolism does not result in the formation of large numbers of potentially carcinogenic substances.”

“After an initiaJ period of HPA axis hyperactivity and cortisol hyper-secretion, hypocortisolism may ultimately develop
as a type of maladaptive “overcompensation” of the self-preservation mechanisms designed to protect the metabolic
machinery (in particular the brain) from the effects of persistent cortisol elevation.”

2. CRF Down regulation

“An increase in the sensitivity of the HPA axis to cortisol during pen~ods of excessive glucocorticoid production
induces negatl.ve feedback control on further release of stimulating hormones, thereby resulting in hypocortisolism”

Inadequate Glucocorticoid Signaling

“Decreased glucocorticoid bioavailability accounts for one possible mechanism and may develop secondary to
decreased adrenal cortisol production, alterations in cortisol binding protein levels, enzymatic conversion of cortisol
to other hormones, or action of the “multidrug resistant pump, ” which potentiates cortisol exit from the cell.”

Intrinsic Adrenal Gland dysfunction

“In the face of adrenocortical atrophy, glucocorticoid production would diminish and compensatory glucocorticoid
receptor up regulation does not occur.

Adaptive Response

“Hypocortisolism may occur as an adaptive survival mechanism to promote a more vigorous immune response,”

“Breast Cancer patients who demonstrate significant post-treatment exhaustion have been shown to have
significantly altered HPA axis activity in combination with elevated IL-6 levels and flattened cortisol curves with an
apparent consequential increase in mortality and metastasis.”

“Diseases such as obesity, increased coronary artery calcification, and metabolic syndrome have been linked to
circadian abnormalities in cortisol, particularly flattened cortisol curves.”

“A number of other small cohort and case-control studies have used HRT in women previously treated for breast cancer without adverse effect. None of these studies has shown an increased risk of recurrence.”

“There was no evidence from this study to indicate any difference in the risk of recurrence of breast cancer for women using topical vaginal estrogen therapy compared with those who use no hormonal therapy.”

“Limited systemic absorption has been reported with the use of vaginal estriol cream or suppositories, while marked systemic absorption can occur with Premarin cream. Endometrial proliferation has not been reported with vaginal estriol preparations.”

“Women with advanced breast cancer and acquired resistance to aromatase inhibitors were given either 6mg or 30mg daily of Estradiol. Patients showed an improvement in their disease when given Estradiol, but the 6 mg dose was better tolerated and had less side effects. “In conclusion, 6 mg of estradiol daily, which produces estradiol levels similar to those in ovulating premenopausal women, is an active low-cost treatment for postmenopausal women with advanced breast cancer and acquired resistance to aromatase inhibitor treatment and should be further investigated.”

“Adding progesterone to E2 significantly reduced the proliferative effect of E2 alone. The present data shows that in vivo, 10 to 13 days of P exposure decreases the growth fraction of normal epithelial cells in the breast of premenopausal women.”

“It also suggests that P or related drugs may have a therapeutic value to prevent breast epithelial hyperplasia when used > 10 days per month at approximate substitutive doses.”

“The association between HRT use and breast cancer risk most likely varies according to the type of progestogen used. There was no or little increase in risk with estrogens used alone or combined with micronized progesterone.”

10. Barrett-Connor, E., et al. “The epidemiology of DHEAS and cardiovascular disease.” Annals of the New York Academy of Sciences, 1995, 774:259-70.

11. “Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study.” Journal of the American Geriatric Society, June 1999, 47 (6): 685-91.

19. Bradlow, H. L., et al. “Indole-3-carbinol: A novel approach to breast cancer prevention.” Appearing in “Cancer Prevention. From the Laboratory to the Clinic: Implications of Genetic, Molecular and Preventive Research,” Annals of the New York Academy of Sciences, September 1995, 768:180-200. And also: “Mulifunctional aspects of the action of indole-3-carbinol as an antitumor agent,” Annals of the New York Academy of Sciences, 1999, 889: 204-13.

“Pathophysiologic consideration in the treatment of menopausal patients with estrogens: the role of estriol in the prevention of mammary carcinoma.” Acta Endocrinol Suppl (Copenhagen), 1980, 233:17-27.

Pierpaoli, Walter. “Melatonin, the pineal gland and aging: A planetary and biological reality.” In the Science of Anti-Ageing Medicine (edited by Klatz and Goldman), Colardo Springs, American Academy of Anti-Ageing Medicine, 1996.

Pierpaoli, Walter, and Regelson, William. “The pineal control of aging. The effect of melatonin and pineal grafting on aging mice.” Proceedings of the National Academy of Sciences, 1994, 91: 787-91.

Seelig, Mildred. “Interrelationship of magnesium and estrogen in cardiovascular and bone disorders, eclampsia, and premenstrual syndrome.” Journal of the American College of Nutrition. 1993, 12 (4): 442-58.